FAK inhibitor and drug combination thereof

Abstract

To provide a FAK inhibitor in the field of tumor treatment with improved pharmacokinetics and reduced metabolic toxicity of the drug.SOLUTION: The present invention provides a compound represented by formula (I-G) or an optical isomer, a tautomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, where, R1 and R5 are selected from hydrogen or a methoxy group, one or more of R1, R5, R20, and R21 are substituted with hydrogen or deuterium, R17, R18, and R19 are substituted with deuterium, and / or R22, R23, and R24 are substituted with deuterium.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to FAK inhibitors and combination drugs thereof. [Background technology]

[0002] Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase that was first discovered in transfected V-Src chicken embryo fibroblasts. FAK is highly expressed in many tissues, and its protein sequence has high homology among many species (e.g., rats, toads, and humans). FAK is involved in multiple biological processes such as tumor formation, proliferation, metastasis, apoptosis, and cardiovascular disease, and is an anti-tumor target that is currently attracting widespread attention.

[0003] Recent studies have revealed that FAK is activated by various factors, such as integrins and G protein-coupled receptors, and that FAK regulates signaling pathways such as P53 and PI3K-AKT-mTOR in cells through two pathways, kinase-dependent and kinase-independent, and is involved in biological processes such as tumor cell survival, proliferation, and metastasis. The first attempt aimed to suppress tumors by downregulating the expression of FAK in tumor cells. Transfecting carboxy-terminal inactivated FAK (FAK-CD) to silence FAK and reduce cell adhesion and proliferation resulted in the inhibition of breast cancer cell proliferation in in vivo experiments. Transfecting a plasmid containing FAK-silenced RNA (FAK-siRNA) also suppresses cancer in vivo. At the same time, the expression of FAK and FAK downstream signal molecules (e.g., SRC) can be suppressed to enhance antitumor effects.

[0004] Due to the important function of FAK in tumor cells, the reliability of gene transfection, and the consideration of the safety of viral vectors, small molecule inhibitors based on the FAK signaling pathway have emerged and have achieved good results in recent years. At present, several FAK inhibitors are used as antitumor drugs and are in the stage of preclinical research or clinical trials. In the literature ("Research progress on antitumor new target focal adhesion kinase FAK and its inhibitors", Chen Ying et al.), it has been reported that TAE226, also known as NVP-226, can inhibit FAK activity by blocking the binding site of FAK and ATP, and the phosphorylation sites of Y397 and Y861 of FAK. However, the field still needs to develop FAK inhibitors with better inhibitory activity or better pharmacodynamic properties.

[0005] Deuterated drugs refer to drugs in which some hydrogen atoms in the drug molecule are replaced with deuterium. Deuterium (D) is a stable isotope of hydrogen. The form and volume of deuterium in drugs are basically the same as those of hydrogen, so even if some hydrogen atoms in drug molecules are replaced with deuterium, the activity of the drug molecule will not change. In addition, the mass of deuterium atoms is twice that of hydrogen, so the zero-point vibration energy of the carbon-deuterium bond (CD) is lower than the zero-point vibration energy of the carbon-hydrogen bond (CH), and the carbon-deuterium bond is more stable. Therefore, by replacing some hydrogen atoms in drug molecules with deuterium, the decomposition process of the drug can be delayed, allowing the deuterated drug to act longer in the body, and achieving the purpose of changing the drug metabolism rate or metabolic pathway, thereby improving the pharmacokinetics and reducing the metabolic toxicity of the drug. In view of the important applications of FAK inhibitors in the field of tumor treatment and their limitations, we have combined the technology of deuterated drugs to find new molecular entities, reduce the impact on liver and kidney function, and improve the safety and Improving the efficacy and efficacy of this class of drugs is a research trend that will drive further development of this class of drugs, and its application is of great value.

[0006] Although drug combination is an effective way to improve therapeutic efficacy, there have been no reports of combining deuterated FAK inhibitors with other anticancer drugs or methods. Summary of the Invention

[0007] To solve the above problems, the present invention provides deuterated compounds and their use as FAK inhibitors, and further provides a concept of combining said deuterated compounds with other anti-cancer drugs.

[0008] The present invention provides a compound of formula (I) or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof: JPEG2025023997000002.jpg4385

[0009] wherein ring S is selected from an aromatic ring or a five-membered heterocycle; A, B, X, Y, and Z are each independently selected from carbon or nitrogen; and E is null or a methylene group; and / or R6 is selected from hydrogen or nothing, R7 is selected from hydrogen, nitrogen or nothing, and R8 is selected from a haloalkyl group or a halogen, or R7 and R8 combine to form a ring; and / or R9 is selected from -NMeSO2Me, -CONHOMe, -CONHMe, amide, hydrogen or nothing; R 10 is selected from hydrogen or nothing, R 11 is selected from -NHSOMe, a halogen, a substituted piperazine, or hydrogen, the substituent on said piperazine being an ethanol group; R 12 is selected from -SO2Me or hydrogen, R 13 is selected from -CONHMe, -CONHOMe, N-alkylsulfonamide, hydrogen or nothing, or R 11 and R 13 are bonded to form a ring, Dx in formula (I) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0010] Preferably, the compound has the structure shown in formula (IA): TIFF2025023997000003.tif4494

[0011] wherein A, B, X, Y, and Z are each independently selected from carbon or nitrogen, and E is null or a methylene group; R1 and R5 are selected from hydrogen or a methoxy group, and R2 and R4 are selected from hydrogen or a methoxy group. R3 is selected from hydrogen, -CONHMe, alkoxyamide, morpholine, methoxy group, ethylamine or sulfonamide; or R2 and R3 are combined to form a ring; or R3 and R4 are combined to form a ring; and / or R6 is selected from hydrogen or nothing, R7 is selected from hydrogen, nitrogen or nothing, and R8 is selected from a haloalkyl group or a halogen, or R7 and R8 combine to form a ring; and / or R9 is selected from -NMeSO2Me, -CONHOMe, -CONHMe, amide, hydrogen or nothing; R 10 is selected from hydrogen or nothing, R 11 is selected from -NHSOMe, a halogen, a substituted piperazine, or hydrogen, the substituent on said piperazine being an ethanol group; R 12 is selected from -SO2Me or hydrogen, R 13 is selected from -CONHMe, N-alkylsulfonamide, hydrogen or nothing, or R 11 and R 13 are bonded to form a ring, or R 13 and R3 and R4 combine to form a ring, Dx in formula (IA) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0012] Preferably, the compound has the structure shown in formula (IB): TIFF2025023997000004.tif3989

[0013] where A, X, and Y are selected from carbon or nitrogen, and E is nothing; R 14 , R 15 , R16 are independently hydrogen, C 1-6 Alkyl group, C 3-6 selected from a cycloalkyl group, a methyl group, an ethyl group, or an isopropyl group; and / or R6 is hydrogen, R7 is hydrogen and R8 is halogen; R9, R 13 is selected from -CONHOMe, -CONHMe or hydrogen; R 10 , R 12 is hydrogen, R 11 is selected from a halogen, hydrogen, or a substituted piperazine, the substituent on said piperazine being an ethanol group; Dx in formula (IB) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0014] Preferably, the compound has the structure shown in formula (IC): TIFF2025023997000005.tif4897

[0015] where A, X, and Y are selected from carbon or nitrogen, and E is selected from a methylene group or nothing. Selected, R9, R 13 is selected from hydrogen, -NMeSO2Me, -CONHOMe or -CONHMe, R 10 , R 12 is hydrogen, and R 11 is selected from hydrogen, a substituted piperazine, or a halogen, the substituent on said piperazine being an ethanol group; and / or R6 is selected from hydrogen, R7 is selected from hydrogen, and R8 is selected from a haloalkyl group or a halogen, or R7 and R8 combine to form a ring; and / or R1, R4, R5 are selected from hydrogen or a methoxy group, R2 is selected from hydrogen or a methoxy group, and R3 is selected from hydrogen, -CONHMe, an alkoxyamide, morpholine, a methoxy group, an ethylamine, or a sulfonamide, or R2 and R3 are combined to form a ring; Dx in formula (IC) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0016] Preferably, the compound has the structure shown in formula (ID): TIFF2025023997000006.tif4386

[0017] Here, R9, R 13 is selected from -CONHOMe, -CONHMe or hydrogen; R 10 , R 12 is hydrogen, and R 11 is selected from halogen, hydrogen or a substituted piperazine, the substituent on said piperazine being an ethanol group; A, X, and Y are selected from carbon or nitrogen, and E is nothing; and / or R6 is selected from hydrogen, R7 is selected from hydrogen and R8 is halogen; and / or R 14 is selected from a methyl group, an ethyl group, or an isopropyl group; R 15 is selected from a methyl group or hydrogen, R 16 is hydrogen, Dx in formula (ID) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0018] Preferably, the compound has the structure shown in formula (IE): TIFF2025023997000007.tif4791

[0019] where B, Z are selected from carbon or nitrogen, E is a methylene group, Y is nitrogen, and X, A are carbon; and / or R6 is nothing, R7 is hydrogen, and R8 is a haloalkyl group; and / or R1, R2 are hydrogen, R3 is -CONHMe, and R4 is hydrogen, or R3 and R4 combine to form a ring; Dx in formula (IE) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0020] Preferably, the compound has the structure shown in formula (IF): TIFF2025023997000008.tif46102

[0021] Here, Dx in formula (IF) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

[0022] Preferably, the compound has the structure shown in formula (IG): TIFF2025023997000009.tif3584

[0023] Here, R1, R5, R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 One or more of are substituted with deuterium.

[0024] Preferably, the compound is selected from, but not limited to, one of the following compounds substituted with deuterium: JPEG2025023997000010.jpg54153JPEG2025023997000011.jpg54159 TIFF2025023997000012.tif60162

[0025] Preferably, the compound is selected from, but not limited to, one of the following compounds or one of the following compounds substituted with deuterium: TIFF2025023997000013.tif53164TIFF2025023997000014.tif51160 TIFF2025023997000015.tif24135 TIFF2025023997000016.tif78159TIFF2025023997000017.tif79163

[0026] The present invention also provides the use of the aforementioned compound or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof in the preparation of a FAK inhibitor, preferably, the FAK inhibitor is a drug for treating cancer.

[0027] wherein the cancer is a solid tumor; The solid tumors include mesothelioma, pancreatic cancer, soft tissue tumors, metastatic tumors, non-solid tumors, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal cancer, genitourinary cancer, prostate cancer, ovarian cancer, the gastrointestinal cancer including colon cancer, the genitourinary cancer including renal, urothelial or testicular cancer, the ovarian cancer including advanced ovarian cancer; The mesothelioma includes neurofibroma, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma, neuroma, adenoid cystic carcinoma, ependymoma, ependymal tumor, malignant pleural tumor, malignant pleural mesothelioma, triplomas, negative breast cancer, non-hematological malignancies, melanoma, colorectal cancer, leukemia, adenocarcinoma, solid tumors; The melanomas include locally advanced melanoma, locally mutated N-Ras-induced melanoma, and metastatic malignant cutaneous melanoma; the colorectal cancers include metastatic colorectal cancer; the leukemias include acute myeloid leukemia; the adenocarcinomas include adenocarcinoma; and the solid tumors include locally advanced solid tumors, metastatic solid tumors, and hepatocellular carcinoma.

[0028] The present invention also provides a combination drug for treating tumors, comprising the aforementioned compound and an anticancer drug for simultaneous or separate administration in the same or different dosage unit formulations, and a pharma- ceutically acceptable carrier.

[0029] The anti-cancer drug is an immunotherapeutic drug, a chemotherapy drug or a radiotherapy drug.

[0030] The immunotherapy drug is selected from a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, an antibody that inhibits CTLA-4, an antibody that inhibits TIM3, an antibody that inhibits LAG3, an antibody that inhibits TIGIT, a checkpoint target blocking antibody, a co-stimulatory antibody, or a CAR-T therapy cell.

[0031] The PD-1 inhibitors or PD-L1 inhibitors include nivolumab, CT-011, AMP-224, pembrolizumab, pidilizumab, MK-3475, BMS936559, MEDI4736, and MSB001071. 8C, MPDL-3280A, SHR-1210, IBI308, BGB-A317, JS001, GLS-010, GB226 geptanolimab, HLX10, AK103, AK104, AK105, AK112, SSI-361, JY034, KN035, SHR1316, TQB2450, KL-A167, CS1001, STI-A1014, JS003, AK106, HLX-09, mPD-1 antibodies, The checkpoint target blocking antibodies include IMP321 and MGA271; The costimulatory antibody includes an anti-4-lBB antibody, an anti-OX40 antibody, an anti-GITR antibody, an anti-CD27 antibody, and an anti-CD40 antibody.

[0032] The chemotherapeutic drug is a toxic drug, an alkylating drug, an antimetabolite, an antibiotic, a hormonal therapy drug, a natural product anticancer drug, a topoisomerase inhibitor, an immunological drug, a platinum complex drug, a kinase inhibitor, an antiproliferative drug, an antibody, an interferon, or a drug that modulates the androgen signaling pathway.

[0033] Such toxic drugs include, but are not limited to, gemcitabine, paclitaxel, and docetaxel; The kinase inhibitors include, but are not limited to, MEK kinase inhibitors, cMet inhibitors, VEGFR2 inhibitors, and EGFR inhibitors; The drugs that regulate the androgen signaling pathway include, but are not limited to, androgen synthesis inhibitors, CYP17A inhibitors, androgen receptor inhibitors, BET inhibitors, BRD4 inhibitors, RORγ inhibitors, CBP / P300 inhibitors, BMX inhibitors, and PARP inhibitors. Preferably, the androgen receptor inhibitors include, but are not limited to, Enzalutamide, Apalutamide, Bicalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119, proxi-alutamide, and SHR3680.

[0034] The present invention also provides a use of the above-mentioned combination drug in the preparation of a drug for treating cancer. do.

[0035] wherein the cancer is a solid tumor; The solid tumors include mesothelioma, pancreatic cancer, soft tissue tumors, metastatic tumors, non-solid tumors, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal cancer, genitourinary cancer, prostate cancer, ovarian cancer, the gastrointestinal cancer including colon cancer, the genitourinary cancer including renal, urothelial or testicular cancer, the ovarian cancer including advanced ovarian cancer; The mesothelioma includes neurofibroma, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma, neuroma, adenoid cystic carcinoma, ependymoma, ependymal tumor, malignant pleural tumor, malignant pleural mesothelioma, triplomas, negative breast cancer, non-hematological malignancies, melanoma, colorectal cancer, leukemia, adenocarcinoma, solid tumors; The melanomas include locally advanced melanoma, locally mutated N-Ras-induced melanoma, and metastatic malignant cutaneous melanoma; the colorectal cancers include metastatic colorectal cancer; the leukemias include acute myeloid leukemia; the adenocarcinomas include adenocarcinoma; and the solid tumors include locally advanced solid tumors, metastatic solid tumors, and hepatocellular carcinoma.

[0036] In the present invention, "alkyl group" includes straight-chain or branched-chain alkyl groups.

[0037] In the present invention, the term "compound of the invention" refers to a compound of formula (I). This term also includes various crystal forms, pharma- ceutically acceptable salts, hydrates or solvates, optical isomers, tautomers, and prodrugs of the compound of formula (I).

[0038] In the present invention, the term "pharmaceutical acceptable salt" refers to a salt suitable for use as a pharmaceutical, which is formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Preferred salts are salts formed by the compound of the present invention and an alkali metal. Alkali metals suitable for forming salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, etc.

[0039] The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to) oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0040] The present invention provides deuterated compounds that exhibit better pharmacokinetics, higher maximum blood concentration, higher exposure and longer half-life, and have better metabolic performance compared with undeuterated compounds. In addition, the deuterated compounds of the present invention can effectively inhibit the activity of FAK, and are very promising for application in the preparation of FAK inhibitors and / or drugs for treating cancer. At the same time, the deuterated compounds of the present invention can exert synergistic effects when combined with anticancer drugs (e.g., PD-1 inhibitors), significantly improving the tumor suppression effect and providing a better option for clinical cancer treatment.

[0041] Naturally, based on the above content of the present invention, various other forms of modifications, substitutions or changes can be made in light of general technical knowledge and conventional means in this field, on the premise that they do not deviate from the above basic technical idea of ​​the present invention.

[0042] The above contents of the present invention will be described in more detail below by embodiments for carrying out the invention in the form of examples. However, this should not be understood as limiting the scope of the above subject matter of the present invention. Any technology realized based on the above contents of the present invention belongs to the scope of the present invention. [Brief description of the drawings]

[0043] [Figure 1] FIG. 1 shows efficacy testing of deuterated compounds of the invention in an animal model of MC38 tumors. [Diagram 2] FIG. 2 shows efficacy testing of deuterated compounds of the invention in an animal model of PAN02 tumors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] All materials and equipment used in this invention were purchased from commercial sources.

[0045] Example 1 Synthesis of N-trideuteromethyl-4-((4-(((3-(N-methylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid amide (Compound 25) TIFF2025023997000018.tif55169

[0046] Step 1: Synthesis of compound 25-2 25-1 (200 mg, 0.39 mmol), DMAP (1.29 g, 10.57 mmol) were added to 10 mL of dichloromethane, and then (Boc)2O (1.71 g, 7.83 mmol) was added dropwise. The system was refluxed in an oil bath for 24 h. The next day, it was cooled to room temperature, dichloromethane and 0.1 N HCl solution were added, extracted, and then allowed to stand for layer separation. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered by suction. The solvent was removed by rotary evaporation, and the crude product was separated by column chromatography to obtain 25-2 (136 mg, yield: 42.8%) as an off-white solid. MS (M+1): 811.2.

[0047] Step 2: Synthesis of compound 25-3 25-2 (136 mg, 0.17 mmol) and deuterated methylamine hydrochloride (189 mg, 2.68 mmol) were added to 5 mL of acetonitrile and stirred at room temperature. Then, DBU (613 mg, 4.03 mmol) was added thereto, and gradually dissolved and clarified. Then, the system was placed in an oil bath and refluxed overnight. The next day, it was cooled to room temperature and the solvent was removed by rotary evaporation, and then dichloromethane and 0.1 N HCl solution were added to the system, vigorously stirred, and allowed to stand for layer separation. The organic phase was washed with purified water and saturated saline respectively, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the mixture was separated and purified by Pre-TLC (PE / EA=2:1) ​​to obtain a white solid 25-3 (42 mg, yield 35.3%). MS (M-Boc+1): 614.2.

[0048] Step 3: Synthesis of compound 25 25-3 (42 mg, 0.06 mmol) was added to 2 mL of dichloromethane and stirred at room temperature (not dissolved, not clarified). Then, 0.1 mL of trifluoromethanesulfonic acid was added thereto to gradually clarify the system, which was then stirred at room temperature overnight to react. The next day, the solvent was removed by rotary evaporation, and ethyl acetate and saturated NaHCO3 solution were added to the system, which was vigorously stirred, and then allowed to stand for layer separation. The pH value of the aqueous phase was measured to be about 7-8. The organic layer was washed twice each with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to give compound 25 (24 mg, yield: 80.0%) as a white solid.

[0049] 1 H NMR(400Hz,DMSO-d6):δ9.863(1H,s),8.688(1H,d,J=2.4Hz),8.581(1H,d,J=2.8Hz),δ8.316(1H,s),δ8.180(1H,s),7.665-7.59 4(4H,dd,J1=19.6Hz,J2=8.8Hz),7.476-7.450(1H,t,J=5.2Hz),δ5.001(2H,d,J=4.8Hz),3.221(3H,s),3.199(3H,s).LC-MS(M+H + ):514.2.

[0050] Compounds 26 to 40 were produced using raw materials according to the compound and a method similar to the method for producing compound 25.

[0051] Example 2 Synthesis of N-methyl-4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid amide (Compound 41) TIFF2025023997000019.tif60154

[0052] Step 1: Synthesis of N-trideuteromethylmethanesulfonamide (compound 41-1) Deuterated methylamine hydrochloride (7.75 g, 109.99 mmol) was placed in a 250 mL one-neck round-bottom flask, dichloromethane (120 mL) was added at the same time, and the mixture was stirred at room temperature. The system was then transferred to an ice-water bath for cooling, and stirred while cooling. After 15 min, triethylamine (21.73 g, 214.75 mmol) and DMAP (128 mg, 1.05 mmol) were added in sequence, and after completion, the system was stirred while maintaining the temperature in an ice-water bath, and reacted for 10 min. Then, methanesulfonyl chloride (12.0 g, 104.76 mmol) was added to the system, and after completion, the ice-water bath was removed, and the system was stirred at room temperature overnight to react. The next day, the completion of the reaction was detected by TLC, and the system was subjected to suction filtration, and the filter cake was eluted several times using small amounts of ethyl acetate, and the filtrates were combined and the solvent was removed by rotary evaporation, after which ethyl acetate (90 mL) was added to the system and stirred vigorously. After 10 min, the system was filtered again under vacuum, and the filter cake was eluted with small portions of ethyl acetate several times, and the filtrates were combined and concentrated in vacuum to give N-trideuteromethylmethanesulfonamide (11.16 g) as a clear, colorless oily liquid. It was used directly in the next reaction without further purification. Yield: 94.9%. LC / MS (ESI+) Calcd for C2H4D3NO2S (M+H+) m / z, 113.1; Found: 113.3.

[0053] Step 2: Synthesis of N-(3-cyanopyrazin-2-yl)-N-trideuteromethylmethanesulfonamide (compound 41-2) N-Trideuteromethylmethanesulfonamide (6.0 g, 53.54 mmol), 2-Chloro-3-cyanopyrazine (6.23 g, 44.62 mmol) was placed in a 500 mL one-neck round-bottom flask, and acetonitrile (300 mL) was added at the same time and stirred at room temperature. Then, cesium carbonate (24.71 g, 75.85 mmol) was added to the system, and after completion, the system was transferred to an 80 °C oil bath and reacted with continued heating and stirring. After 1.5 h, a sample was dropped onto the plate, and TLC showed that the raw material was completely consumed. Heating was stopped and the system was cooled naturally to room temperature. The system was subjected to suction filtration, and the filter cake was eluted with small amounts of acetonitrile multiple times, and the filtrates were combined and the solvent was removed by rotary evaporation. Then ethyl acetate (150mL) and water (150mL) were added to the system, stirred vigorously, and allowed to stand to separate the layers. The aqueous phase was back-extracted with ethyl acetate (50mL*3), and the organic phases were combined, washed with purified water (30mLx3) and saturated saline (30mL) in sequence, dried over anhydrous sodium sulfate, and concentrated in vacuum to obtain a crude product. This was separated and purified by column chromatography to obtain a light reddish-brown oily liquid of N-(3-cyanopyrazin-2-yl)-N-deuteromethylmethanesulfonamide (5.29g). Yield: 55.1%. LC / MS(ESI+)Calcd for C7H5D3N4O2S(M+H+)m / z,216.1;Found:233.1(M+H2O). 1H NMR (400MHz, DMSO-d6) δ8.65-8.63 (dd, J=6.0, 2.4Hz, 2H), 3.26 (s, 3H).

[0054] Step 3: Synthesis of N-(3-(aminomethyl)pyrazin-2-yl)-N-trideuteromethylmethanesulfonamide (compound 41-3) N-(3-cyanopyrazin-2-yl)-N-deuteromethylmethanesulfonamide (2.0 g, 9.30 mmol) was weighed into a 500 mL one-neck round-bottom flask, methanol (270 mL) was added thereto, and the mixture was stirred at room temperature to dissolve and clarify. Then, wet palladium on carbon (1 g) and aqueous ammonia (20 mL) were added to the system. Next, the system was evacuated and argon gas was introduced five times to ensure an inert gas atmosphere in the system. Then, a hydrogen replacement operation was performed on the system, and after completion, the reaction was continued by stirring at room temperature. After 5 h, a sample was dropped onto the plate, and TLC showed that the raw material had been completely consumed. The reaction was stopped and the hydrogenation apparatus was removed. The system was subjected to suction filtration, and the filter cake was repeatedly eluted with methanol several times. The filtrates were combined and the solvent was removed by rotary evaporation. Furthermore, the residual water in the system was removed several times by spinning band using methanol to obtain a light tan transparent oily liquid of N-(3-(aminomethyl)pyrazin-2-yl)-N-deuteromethylmethanesulfonamide. This was used directly in the next reaction without further purification. LC / MS(ESI+)Calcd for C7H9D3N4O2S(M+H+)m / z,220.1; Found:220.1.

[0055] Step 4: Synthesis of compound tert-butyl (4-(methylcarbamoyl)phenyl)carbamate 4-((tert-butoxycarbonyl)amino)benzoic acid (3.0 g, 12.65 mmol) was weighed into a 250 mL single-neck round-bottom flask, 50 mL of DMF was added thereto, and stirred at room temperature. EDCI (4.8 g, 25.29 mmol), TEA (4.5 g, 44.28 mmol), methylamine hydrochloride (1.3 g, 18.98 mmol), and DMAP (16.0 mg, 0.13 mmol) were then added to the system in that order. After completion, the system was allowed to react at room temperature overnight with stirring. The next day, it was confirmed by monitoring that all the raw materials had been consumed, and ethyl acetate (70 mL) and water (50 mL) were added to the system, vigorously stirred, and allowed to stand to separate into layers. The aqueous phase was back-extracted with ethyl acetate (20 mL*3), and the organic layers were combined, washed with water (20 mL*3) and saturated saline (30 mL), respectively, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a crude product. It was then separated by column chromatography to obtain 2.1 g of off-white solid tert-butyl (4-(methylcarbamoyl)phenyl)carbamate. Yield: 66.5%. MS(ESI)m / e25 1.2(M+H) + .

[0056] Step 5: Synthesis of compound 4-amino-N-methylbenzamide trifluoroacetate tert-Butyl (4-(methylcarbamoyl)phenyl)carbamate (500.0 mg, 2.00 mmol) was weighed into a 50 mL one-neck round-bottom flask, 10 mL of dichloromethane was added thereto, and the mixture was stirred at room temperature. Then, trifluoroacetic acid (1 mL) was added to the system, and after completion, the system was stirred at room temperature overnight to react. The next day, TLC showed that the reaction was completed. The solvent and excess trifluoroacetic acid were removed by concentration, and the remaining trifluoroacetic acid in the system was removed by spinning band using dichloromethane several times until the system was completely solid, and 4-amino-N-methylbenzamide trifluoroacetate (510.0 mg) was obtained as a white-ish solid. This was used as it was in the next reaction without further purification.

[0057] Step 6: Synthesis of compound 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (499.0 mg, 2.30 mmol) was weighed into a 50 mL one-necked round-bottom flask, and 1,2-dichloroethane (5 mL) and tert-butanol (5 mL) were added to the system, and the mixture was stirred at room temperature to dissolve and clarify. The system was then transferred to an ice-water bath, cooled, and stirred while the temperature was lowered, and after 15 min, zinc bromide (1.4 g, 6.00 mmol) was added to the system. After completion, the system was stirred for 30 min while maintaining the temperature in an ice-water bath. Then, 4-amino-N-methylbenzamide trifluoroacetate and triethylamine (648.0 mg, 6.40 mmol) synthesized in the previous step were added to the system. After addition, the ice-water bath was removed, and the system was stirred at room temperature overnight to react. The next day, the reaction was confirmed to be complete by monitoring, the solvent was removed by rotary evaporation, ethyl acetate (30 mL) and water (20 mL) were added to the system, vigorously stirred, and allowed to stand to separate the layers. The aqueous layer was back-extracted with ethyl acetate (10 mL * 3), the organic phases were combined, washed with water (15 mL * 3) and saturated saline (15 mL) in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This was then separated by column chromatography to obtain 280.0 mg of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide as an off-white solid. Yield: 42.3%. MS (ESI) m / e 331.0 (M + H) + .

[0058] Step 7: Synthesis of compound N-methyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido group)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide In a 25 mL one-necked round-bottom flask containing N-(3-(aminomethyl)pyrazin-2-yl)-N-deuteromethylmethanesulfonamide (compound 41-3, 65.8 mg, 0.30 mmol), 5 mL of 1,2-dichloroethane and 5 mL of tert-butanol were added and stirred at room temperature to dissolve and clarify. Then, 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide (100.0 mg, 0.30 mmol) and diisopropylethylamine (116.3 mg, 0.90 mmol) were added in sequence to the system, and after addition, the system was transferred to an 80 ° C oil bath and refluxed. After 8 h, TLC monitoring confirmed that the raw material was completely consumed. After heating was stopped and the system was cooled to room temperature, the solvent was removed by rotary evaporation to obtain the crude product. This was then separated and purified by Pre-TLC to obtain 12 mg of off-white solid N-methyl-4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (compound 41). Yield: 7.8%. MS (ESI) m / e 514.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.69(s,1H),8.59(s,1H),8.32(s,1H),8.20(d ,J=4.0Hz,1H),7.68-7.61(dd,J=14.4,8.4Hz,4H),7.41-7.39(t,J=4.4Hz,1H),5.01(d,J=3.6Hz,2H),3.20(s,3H),2.76(d,J=4.0Hz,3H).

[0059] Compounds 42 and 43 were prepared using starting materials according to the compound and a method similar to that for compound 41.

[0060] Example 3 Synthesis of N-trideuteromethyl-4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid amide (Compound 44) ​​and its hydrochloride salt TIFF2025023997000020.tif58159

[0061] Step 1: Synthesis of tert-butyl (4-(trideuteromethylcarbamoyl)phenyl)carbamate (compound 44-1) N-Boc-4-aminobenzoic acid (6.0g, 25.29mmol), EDCI (7.27g, 37.93mmol) were weighed into a 250mL one-neck round-bottom flask, DMF (50mL) was added at the same time, and the mixture was stirred at room temperature. Then, triethylamine (6.40g, 63.22mmol), deuterated methylamine hydrochloride (1.96g, 27.82mmol) were added to the system, and after completion, the system was stirred at room temperature overnight to react. The next day, a sample was dropped onto the plate, and TLC showed that the reaction was complete. Ethyl acetate (50mL), water (50mL) were added to the system, and the mixture was stirred vigorously, then left to stand for layer separation, and the aqueous phase was back-extracted with ethyl acetate (50mL*3), and the organic phase was combined, washed with water (30mL*3), saturated saline (50mL) in sequence, dried over anhydrous sodium sulfate, and concentrated in vacuum to obtain the crude product. This was separated and purified by column chromatography to obtain off-white solid tert-butyl (4-(deuteromethylcarbamoyl)phenyl)carbamate (4.92 g). Yield: 76.8%. LC / MS (ESI+) Calcd for C13H15D3N2O3 (M+H+) m / z, 254.2; Found: 254.2.

[0062] Step 2: Synthesis of 4-amino-N-trideuteromethylbenzamide trifluoroacetate (compound 44-2) tert-Butyl (4-(deuteromethylcarbamoyl)phenyl)carbamate (3.0 g, 11.84 mmol) was weighed into a 100 mL one-neck round-bottom flask, and dichloromethane (15 mL) was added at the same time and stirred at room temperature. Then trifluoroacetic acid (7 mL) was added to the system, and after completion, the system was stirred at room temperature to react. After 5 h, the sample was dropped onto the plate, and TLC showed that the reaction was complete. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and the residual trifluoroacetic acid was repeatedly removed by spinning band with dichloromethane to obtain an off-white solid 4-amino-N-deuteromethylbenzamide trifluoroacetate. It was used directly in the next reaction without further purification. This was used.

[0063] Step 3: Synthesis of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-trideuteromethylbenzamide (compound 44-3) 2,4-Dichloro-5-trifluoromethylpyrimidine (2.83g, 13.02mmol) was weighed into a 100mL one-neck round-bottom flask, and 1,2-dichloroethane (30mL) and tert-butanol (30mL) were added at the same time, and the mixture was stirred at room temperature to dissolve and clarify. The system was then transferred to an ice-water bath to cool, and continued to stir while cooling. After the temperature in the system had dropped to about 0°C, zinc bromide (8.0g, 35.52mmol) was added to the system, and after completion, the system was reacted for 30min while maintaining the temperature in an ice-water bath. Then, 4-amino-N-deuteromethylbenzamide trifluoroacetate and triethylamine (3.83g, 37.89mmol) prepared in the reaction of the previous step were added to the system, and then the ice-water bath was removed, and the system was stirred and reacted at room temperature overnight. The next day, a sample was dropped onto the plate, and TLC showed that the raw materials had been completely consumed, and the reaction was stopped. The solvent was removed by rotary evaporation, and ethyl acetate (50 mL) and water (30 mL) were added to the system, stirred vigorously, and then allowed to stand for layer separation. The aqueous phase was back-extracted with ethyl acetate (30 mL*3), and the organic phases were combined, washed with water (30 mL*3) and saturated saline (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated in vacuum to obtain a crude product. This was separated and purified by column chromatography to obtain a white-ish solid 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-deuteromethylbenzamide (3.23 g). Yield of the reaction of steps 2 to 3: 81.8%.

[0064] LC / MS(ESI+)Calcd for C13H7D3ClF3N4O(M+H+)m / z,334.0;Found:334.0.1H NMR (400MHz, DMSO-d6) δ10.89(s, 1H), 8.87(s, 1H), 8.31(s, 1H), 7.84-7.77(m, 4H).

[0065] Step 4: Synthesis of N-trideuteromethyl-4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (compound 44) 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-deuteromethylbenzamide (3.1 g, 9.29 mmol), N-(3-cyanopyrazin-2-yl)-N-deuteromethylmethanesulfonamide (2.0 g, 9.29 mmol) were weighed into a 250 mL one-neck round-bottom flask, then 1,2-dichloroethane (80 mL) and tert-butanol (80 mL) were added thereto, and stirred at room temperature to dissolve and clarify. After that, diisopropylethylamine (3.6 g, 27.87 mmol) was added to the system, and after completion, the system was transferred to an 80 °C oil bath to reflux, stir, and react overnight. The next day, a sample was dropped onto the plate, and TLC showed that the reaction was complete. The solvent was removed by rotary evaporation, and ethyl acetate (100 mL) and water (50 mL) were added to the system, stirred vigorously, and then allowed to stand to separate into layers. The aqueous phase was back-extracted with ethyl acetate (50 mL*3), and the organic phases were combined, washed with water (30 mL*3) and saturated saline (50 mL) in that order, dried over anhydrous sodium sulfate, and concentrated in vacuum to obtain a crude product. This was separated and purified by column chromatography to obtain the target compound (2.36 g) as a white-ish solid. This solid was then placed in a 250 mL one-neck round-bottom flask, ethyl acetate (75 mL) was added, and the mixture was stirred at room temperature to form a slurry. After 3 h, the cake was filtered under suction, and the filter cake was eluted with small portions of ethyl acetate (45 mL) several times, and then dried at low temperature in a vacuum drying oven to obtain white solid N-deuteromethyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (2.11 g). Yield: 44.0%. LC / MS (ESI+)Calcd for C20H15D6F3N8O3S(M+H+)m / z,517.2;Found:517.2.1H NMR(400MHz,DMSO)δ9.83(s,1H),8.69(d,J=2.8Hz,1H),8.58(d,J=2.4Hz,1H),8.31(s,1H),8.17(s ,1H),7.67-7.61(dd,J=15.4,8.6Hz,4H),7.41(t,J=5.0Hz,1H),5.00(d,J=4.8Hz,2H),3.20(s,3H).

[0066] Step 5: Synthesis of N-deuteromethyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide hydrochloride Compound 44 (500 mg, 0.97 mmol) was weighed into a 100 mL one-neck round-bottom flask, methanol (25 mL) was added thereto, and the mixture was stirred uniformly at room temperature. Then, hydrogen chloride in ethanol (2.25 mL, 2.0 M) was slowly dropped into the system, and after completion, the system was continuously stirred at room temperature to react. After 1.5 h, the system was subjected to suction filtration, and the filter cake was eluted several times with small amounts of methanol (15 mL), which was then placed in a vacuum drying oven and dried at low temperature to obtain off-white solid N-deuteromethyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl hydrochloride (517 mg). Yield: 96.6%. LC / MS(ESI+)Calcd for C20H16D6ClF3N8O3S(M+H+)m / z,517.2;Found:517.2.1H NMR(400MHz,DMSO)δ10.02(s,1H),8.68(d,J=2.8Hz,1H),8.58(d,J=2.4Hz,1H),8.35(s ,1H),8.21(s,1H),7.67-7.57(m,5H),5.26(br,6H)5.00(d,J=4.8Hz,2H),3.19(s,3H).

[0067] Example 4 Synthesis of N-deuteromethyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)deuteromethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino))benzamide (Compound 45) TIFF2025023997000021.tif45169

[0068] Step 1: Synthesis of compound N-(3-(aminodideuteromethyl)pyrazin-2-yl)-N-deuteromethylmethanesulfonamide (45-1) Compound 41-2 (100.0 mg, 0.46 mmol) was weighed into a 25 mL one-neck round-bottom flask, and 5 mL of deuterated methanol was added, and the mixture was stirred at room temperature to dissolve and clarify. Then, 20.0 mg of wet palladium carbon (treated with deuterium oxide) and triethylamine (188.2 mg, 1.86 mmol) were added to the system in order, and the system was subjected to hydrogen replacement 10 times. After completion, the system was stirred at room temperature to react. After 72 h, the reaction was confirmed to be complete by monitoring. The system was subjected to suction filtration, and the filter cake was eluted multiple times with small amounts of deuterated methanol (10 mL). The filtrates were combined, and the solvent was removed by rotary evaporation to obtain N-(3-(aminodeuteromethyl)pyrazin-2-yl)-N-deuteromethylmethanesulfonamide as a light yellow-brown oily liquid. This was used directly in the next reaction without further purification. MS(ESI)m / e222 .2(M+H) + .

[0069] Step 2: Synthesis of compound N-deuteromethyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)deuteromethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino))benzamide (45) 2mL of 1,2-dichloroethane and 2mL of tert-butanol were added to a 25mL one-necked round-bottom flask containing N-(3-(aminodeuteromethyl)pyrazin-2-yl)-N-deuteromethylmethanesulfonamide (22.1mg, 0.10mmol), and the mixture was stirred at room temperature to dissolve and clarify. Compound 44-3 (33.4mg, 0.10mmol) and diisopropylethylamine (30.6mg, 0.30mmol) were then added to the system in that order, and after addition, the system was transferred to an 80°C oil bath and refluxed. After 8h, TLC monitoring confirmed that the raw materials had been completely consumed. Heating was stopped, the system was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain a crude product, which was then separated and purified by Pre-TLC to obtain 8.1 mg of off-white solid N-deuteromethyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino))benzamide. Yield: 15.6%. MS(ESI)m / e519.2(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.69(d,J=2.0Hz,1H),8.58(d,J=2.4Hz,1H),8. 31(s,1H),8.17(s,1H),7.67-7.61(dd,J=15.2,8.8Hz,4H),7.39(s,1H),3.20(s,3H).

[0070] Example 5 Synthesis of 4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (Compound 52) TIFF2025023997000022.tif36170

[0071] Step 1: Synthesis of compound 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (52-2) 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (434 mg, 2.00 mmol) was weighed into a 50 mL one-neck round-bottom flask, and 1,2-dichloroethane (5 mL) and tert-butanol (5 mL) were added to the system, and the mixture was stirred at room temperature to dissolve and clarify. The system was then transferred to an ice-water bath, cooled, and stirred while the temperature was lowered, and after 15 min, zinc bromide (1.2 g, 5.22 mmol) was added to the system. After completion, the system was stirred for 30 min in an ice-water bath while maintaining the temperature. Then, 4-aminobenzamide (237 mg, 1.74 mmol) and triethylamine (564 mg, 5.57 mmol) synthesized in the previous step were added to the system. After addition, the ice-water bath was removed, and the system was stirred at room temperature overnight to react. The next day, the reaction was confirmed to be complete by monitoring, the solvent was removed by rotary evaporation, ethyl acetate (30 mL) and water (20 mL) were added to the system, vigorously stirred, and allowed to stand to separate the layers. The aqueous layer was back-extracted with ethyl acetate (10 mL * 3), the organic phases were combined, washed with water (15 mL * 3) and saturated saline (15 mL) in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This was then separated by column chromatography to obtain 294 mg of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide as an off-white solid. Yield: 53.4%. MS (ESI) m / e317.0(M+H) + .

[0072] Step 2: Synthesis of compound 4-((4-(((3-(N-trideuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (52) 5mL of 1,2-dichloroethane and 5mL of tert-butanol were added to the 25mL one-necked round-bottom flask containing the compound 52-2 prepared above, and the mixture was stirred at room temperature to dissolve and clarify. Then, compound 44-3 (63.0mg, 0.20mmol) and diisopropylethylamine (78mg, 0.60mmol) were added to the system in order, and after addition, the system was transferred to an oil bath at 80°C for reflux reaction. The next day, TLC monitoring confirmed that the raw materials were completely consumed. After stopping heating and cooling the system to room temperature, the solvent was removed by rotary evaporation to obtain a crude product, which was then separated and purified by Pre-TLC to obtain 22mg of off-white solid 4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino))benzamide. Yield: 22.0%. MS(ESI) m / e500.1(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.69(s,2H),8.60(s,1H),8.31(s,1H),8.20(d,J=4.0Hz,1H), 7.68-7.60(dd,J=15.4,8.4Hz,4H),7.41-7.39(t,J=4.4Hz,1H),5.03(d,J=3.6Hz,2H),3.20(s,3H).

[0073] The known compounds 4-amino-3,5-dideuterobenzoic acid and 4-amino-2,6-dideuterobenzoic acid (Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 668-673;2010) were used as raw materials, and compounds 48-50 and 53-55 were prepared according to the methods of the above examples. The known compounds 4-amino-2,3,5,6-tetradeuterobenzoic acid (Journal of Natural Products, 79(6), 1532-1537;2016) were used as raw materials, and compounds 59-61 were prepared according to the methods of the above examples.

[0074] The following test examples demonstrate the beneficial effects of the present invention.

[0075] Test Example 1: Inhibitory activity of the deuterated compound of the present invention against FAK (1) Test method The FAK enzyme inhibitory activity experiment was carried out with reference to the literature method (Cancer Res. 2008, 68, 1935). Specifically, the test compound was diluted to 1000 nM, then serially diluted with DMSO at a ratio of 1:3, and 0.1 L of the solution was taken and placed in a 384-well plate, with two wells for each concentration. 5 L of 2x FAK enzyme solution was added, centrifuged at 1000 rpm for 1 minute, and incubated at 25 ° C for 15 minutes. 5 L of 2x substrate solution was added and incubated at 25 ° C for 60 minutes. Furthermore, 5 L of Sa-XL665 solution and 5 μL of TK antibody-Eu3+ were added, centrifuged at 1000 rpm for 1 minute, and incubated at 25 ° C for 60 minutes, and finally the fluorescent signal was read using an Envision 2104 plate reader, and the 50% inhibitory concentration IC50 of each compound against the FAK enzyme was calculated. The known FAK inhibitor defactinib was used as a control.

[0076] (2) Test results The inhibitory activity of each compound against FAK is shown in Table 1. The compounds prepared according to the present invention can effectively inhibit the activity of FAK enzyme, and the deuterated compounds 41 and 45 of the present invention have a higher inhibitory activity against FAK enzyme than the non-deuterated compound defactinib. was found to be more active.

[0077] [Table 1]

[0078] Test Example 2 Pharmacokinetic test of the deuterated compound of the present invention in rats (1) Test method An appropriate amount of test drug (10 mg) was precisely weighed out, and 0.25 ml of N,N-dimethylacetamide (DMA) was added to dissolve it, and then 0.5% sodium carboxymethylcellulose (CMC-Na) was slowly added up to 5 ml, and mixed uniformly by ultrasonic or vortex. 0.2 ml of the final solution prepared above was taken and stored at -20°C for concentration measurement.

[0079] Three healthy male adult SD rats (180-250g, purchased from Chengdu Dashuo Laboratory Animal Co., Ltd.) were fasted overnight (free water intake) and then administered intragastrically at a volume of 5ml / kg. 0.1ml of blood was collected from the retroorbital venous plexus before administration and 0.5, 1, 2, 4, 6, 8, 12, and 24h after administration, and plasma was separated by centrifugation at 4℃ for 5min and stored at -20℃ for measurement. The concentration of the test compound in plasma was then measured by LC / MS / MS. The known FAK inhibitor defactinib was used as a control.

[0080] (2) Test results

[0081] [Table 2]

[0082] As shown in Table 2, the deuterated compounds 25 and 44 prepared in the present invention show better pharmacokinetics than defactinib, and the compounds of the present invention have higher maximum blood concentration Cmax, higher exposure AUC, and longer half-life. Therefore, the deuterated compounds prepared in the present invention have a brighter application prospect in FAK inhibitors or drugs for treating cancer.

[0083] Test Example 3: Efficacy test of the combination of the deuterated compound of the present invention and a PD-1 inhibitor in a tumor animal model 1.MC38 tumor model: (1) Test method Cell culture: MC-38 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS). MC-38 cells in the logarithmic growth phase were harvested, resuspended in HBSS to an appropriate concentration, and used for subcutaneous tumor inoculation in C57BL / 6 mice.

[0084] Experimental animals: C57BL / 6 mice, female, 6-8 weeks old, weighing approximately 18-20 g, 96 mice, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0085] Tumor cell inoculation: Collect tumor cells in the logarithmic growth phase and adjust the cell concentration to 5 × 10 in HBSS. 6 The solution was adjusted to 5 × 10 / mL, and 0.1 mL was inoculated subcutaneously into the right side of each mouse near the back using a 1 mL syringe. 5 The tumor volume was then observed and measured, and the average tumor volume of the mice was 50-100 mm 3 After the tumors had grown to 100 mg / kg, the tumor-bearing mice were randomly grouped and administered according to the tumor volume. The detailed information is shown in Table 3 below, and the day of grouping and administration was defined as day 0.

[0086] Calculation of tumor volume: On day 18, the mice were sacrificed, the tumors were removed and the tumor volumes were measured, and the tumor inhibition rates of each group were calculated.

[0087] [Table 3]

[0088] (2) Test results The efficacy after 18 days of administration to animals is shown in Figure 1, and the calculated tumor inhibition rate is shown in Table 3. It was found that the efficacy of compound 44 of the present invention alone was superior to that of the mPD-1 antibody alone, indicating that the compound of the present invention has a therapeutic effect on MC38 tumor model mice when administered alone.

[0089] In addition, when compound 44 was administered in combination with mPD-1 antibody (Group 5), the tumor-suppressing effect was significantly improved compared with compound 44 alone (Group 4) or mPD-1 antibody alone (Group 2), and a synergistic effect was exhibited.

[0090] In addition, when compound 44 of the present invention (50 mg / kg, administered once a day) was administered in combination with an mPD-1 antibody (Group 5), the tumor-suppressing effect was higher and more excellent than when Defactinib (50 mg / kg, administered twice a day) was administered in combination with an mPD-1 antibody (Group 3). That is, when administered in combination with a PD-1 inhibitor, the compound of the present invention exhibited more excellent tumor-suppressing effect at half the dose of Defactinib. The results showed that the combination of the compound of the present invention with a PD-1 inhibitor had a significantly superior antitumor effect against the MC38 tumor model compared to the combination of Defactinib with a PD-1 inhibitor.

[0091] 2.PAN02 Tumor Model (1) Test method PAN-02 cells in the logarithmic growth phase were harvested, washed twice with PBS, and then resuspended in pre-cooled PBS for inoculation. The experimental animals were female C57BL / 6 mice purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd. The C57BL / 6 mice were adapted to the laboratory environment for 3 days and then subcutaneously inoculated with PAN-02 cells in the right flank, with the inoculated cell volume being 1 × 10 6 The tumor size was approximately 100 mm 3 After they had grown to adulthood, they were screened and randomly divided into groups of 8 mice each, and administered according to the groups and administration schedules in Table 4 below. The day they were divided into groups and administered was defined as day 1, and the administration period was 33 days.

[0092] [Table 4]

[0093] (2) Test results The efficacy after 33 days of administration to animals is shown in Figure 2, and the calculated tumor inhibition rates are shown in Table 4. When compound 44 was administered in combination with mPD-1 antibody (Group 5), the tumor inhibition effect was significantly improved compared to when compound 44 was administered alone (Group 4) or mPD-1 antibody was administered alone (Group 2).

[0094] On the other hand, when compound 44 of the present invention (25 mg / kg, administered twice a day) was administered in combination with mPD-1 antibody (Group 5), the tumor suppression effect was significantly improved compared to when Defactinib (50 mg / kg, administered twice a day) was administered in combination with mPD-1 antibody (Group 3). That is, when administered in combination with a PD-1 inhibitor, the compound of the present invention exhibited a superior tumor suppression effect at a lower dose than Defactinib, indicating that the combination of the compound of the present invention and a PD-1 inhibitor has a significantly superior antitumor effect against the PAN-02 tumor model than the combination of Defactinib and a PD-1 inhibitor.

[0095] As described above, the present invention provides deuterated compounds that exhibit better pharmacokinetics, higher maximum blood concentration, higher exposure, and longer half-life, and have better metabolic performance, compared to undeuterated compounds. Furthermore, the deuterated compounds of the present invention can effectively inhibit the activity of FAK, and are useful for the preparation of FAK inhibitors and / or drugs for treating cancer. At the same time, the deuterated compounds of the present invention can exert synergistic effects in combination with anticancer drugs (such as PD-1 inhibitors), significantly improving the tumor suppression effect and providing a better option for clinical cancer treatment.

Claims

1. A compound of formula (I) or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, wherein ring S is selected from an aromatic ring or a five-membered heterocycle; A, B, X, Y, and Z are each independently selected from carbon or nitrogen; E is null or a methylene group; and / or R ６ is selected from hydrogen or nothing; R ７ is selected from hydrogen, nitrogen or nothing; R ８ is selected from haloalkyl groups or halogens, or R ７ and R ８ are bonded to form a ring, and / or R ９ -NMeSO ２ Me, -CONHOMe, -CONHMe, amide, hydrogen or nothing; R １０ is selected from hydrogen or nothing; R １１ Ha-NHSO ２ Me, halogen, substituted piperazine, or hydrogen, wherein the substituent on the piperazine is an ethanol group; R １２ Ha-SO ２ Me or hydrogen; R １３ is selected from -CONHMe, -CONHOMe, N-alkylsulfonamide, hydrogen or nothing; or R １１ and R １３ are bonded to form a ring, Dx in formula (I) represents that hydrogen on at least one carbon atom of the compound in the brackets is replaced with deuterium, and x is an integer of 1 or more, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof.

2. The compound has the structure shown in formula (IA): wherein A, B, X, Y, and Z are each independently selected from carbon or nitrogen, and E is null or a methylene group; R １ , R ５ is selected from hydrogen or a methoxy group; R ２ , R ４ is selected from hydrogen or a methoxy group; R ３ is selected from hydrogen, -CONHMe, an alkoxyamide, a morpholine, a methoxy group, an ethylamine or a sulfonamide, or R ２ and R ３ are bonded to form a ring, or R ３ and R ４ are bonded to form a ring, and / or R ６ is selected from hydrogen or nothing; R ７ is selected from hydrogen, nitrogen or nothing; R ８ is selected from haloalkyl groups or halogens, or R ７ and R ８ are bonded to form a ring, and / or R ９ -NMeSO ２ Me, -CONHOMe, -CONHMe, a mido, hydrogen or nothing; R １０ is selected from hydrogen or nothing; R １１ Ha-NHSO ２ Me, halogen, substituted piperazine, or hydrogen, wherein the substituent on the piperazine is an ethanol group; R １２ Ha-SO ２ Me or hydrogen; R １３ is selected from -CONHMe, N-alkylsulfonamide, hydrogen or nothing, or R １１ and R １３ are bonded to form a ring, or R １３ and R ３ and R ４ are bonded to form a ring, The compound according to claim 1, wherein Dx in formula (IA) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof.

3. The compound has the structure shown in formula (IB): where A, X, and Y are selected from carbon or nitrogen, and E is nothing; R １４ , R １５ , R １６ are independently hydrogen, C １－６ Alkyl group, C ３－６ selected from a cycloalkyl group, a methyl group, an ethyl group, or an isopropyl group; and / or R ６ is hydrogen, R ７ is hydrogen, R ８ is a halogen, R ９ , R １３ is selected from -CONHOMe, -CONHMe or hydrogen; R １０ , R １２ is hydrogen, R １１ is selected from a halogen, hydrogen, or a substituted piperazine, the substituent on said piperazine being an ethanol group; The compound according to claim 1, wherein Dx in formula (IB) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof.

4. The compound has the structure shown in formula (IC): wherein A, X, and Y are selected from carbon or nitrogen, and E is selected from a methylene group or nothing; R ９ , R １３ is hydrogen, -NMeSO ２ R is selected from -Me, -CONHOMe or -CONHMe; １０ , R １２ is hydrogen, R １１ is hydrogen, substituted piperazine or halo a substituent on said piperazine is an ethanol group; and / or R ６ is selected from hydrogen, R ７ is selected from hydrogen, R ８ is selected from haloalkyl groups or halogens, or R ７ and R ８ are bonded to form a ring, and / or R １ , R ４ , R ５ is selected from hydrogen or a methoxy group; R ２ is selected from hydrogen or a methoxy group; R ３ is selected from hydrogen, -CONHMe, an alkoxyamide, a morpholine, a methoxy group, an ethylamine or a sulfonamide, or R ２ and R ３ are bonded to form a ring, The compound according to claim 2, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein Dx in formula (IC) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

5. The compound has the structure shown in formula (ID): Here, R ９ , R １３ is selected from -CONHOMe, -CONHMe or hydrogen; R １０ , R １２ is hydrogen, R １１ is selected from halogen, hydrogen or a substituted piperazine, the substituent on said piperazine being an ethanol group; A, X, and Y are selected from carbon or nitrogen, and E is nothing; and / or R ６ is selected from hydrogen, R ７ is selected from hydrogen, R ８ is a halogen, and / or R １４ is selected from a methyl group, an ethyl group, or an isopropyl group; R １５ is selected from a methyl group or hydrogen; R １６ is hydrogen, The compound according to claim 3, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein Dx in formula (ID) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

6. The compound has the structure shown in formula (IE): wherein B, Z are selected from carbon or nitrogen, E is a methylene group, Y is nitrogen, and X, A are carbon; and / or R ６ is not present, and R ７ is hydrogen, R ８ is a haloalkyl group 、 and / or R １ , R ２ is hydrogen, R ３ is -CONHMe, R ４ is hydrogen, or R ３ and R ４ are bonded to form a ring, The compound according to claim 1, wherein Dx in formula (I-E) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof.

7. The compound has a structure shown in formula (I-F): The compound according to claim 6, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein Dx in formula (I-F) represents that hydrogen on at least one carbon atom of the compound in parentheses is replaced with deuterium, and x is an integer of 1 or more.

8. The compound has a structure shown in formula (IG): Here, R １ , R ５ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, according to claim 7, characterized in that one or more of:

9. The compound is selected from, but not limited to, one of the following compounds substituted with deuterium: Preferably, the compound according to any one of claims 1 to 8, or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, characterized in that the compound is selected from, but not limited to, one of the following compounds or one of the following compounds substituted with deuterium:

10. 10. Use of a compound according to any one of claims 1 to 9 or an optical isomer, tautomer, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof in the preparation of a FAK inhibitor, preferably wherein said FAK inhibitor is a drug for treating cancer.

11. the cancer is a solid tumor; The solid tumors include mesothelioma, pancreatic cancer, soft tissue tumors, metastatic tumors, non-solid tumors, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal cancer, genitourinary cancer, prostate cancer, ovarian cancer, the gastrointestinal cancer including colon cancer, the genitourinary cancer including renal, urothelial or testicular cancer, the ovarian cancer including advanced ovarian cancer; The mesothelioma includes neurofibroma, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma, neuroma, adenoid cystic carcinoma, ependymoma, ependymal tumor, malignant pleural tumor, malignant pleural mesothelioma, triplomas, negative breast cancer, non-hematological malignancies, melanoma, colorectal cancer, leukemia, adenocarcinoma, solid tumors; The use of claim 10, wherein the melanoma includes locally advanced melanoma, locally mutated N-Ras-induced melanoma, metastatic malignant cutaneous melanoma, the colorectal cancer includes metastatic colorectal cancer, the leukemia includes acute myeloid leukemia, the adenocarcinoma includes adenocarcinoma, and the solid tumors include locally advanced solid tumors, metastatic solid tumors, and hepatocellular carcinoma.

12. A combination drug for treating a tumor, comprising a compound according to any one of claims 1 to 9 and an anticancer drug, which are administered simultaneously or separately in the same or different standardized unit dosage form, and a pharma- ceutically acceptable carrier.

13. The combination drug of claim 12, wherein the anti-cancer drug is an immunotherapy drug, a chemotherapy drug, or a radiotherapy drug.

14. The combination drug of claim 13, wherein the immunotherapy drug is selected from a checkpoint inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, an antibody that inhibits CTLA-4, an antibody that inhibits TIM3, an antibody that inhibits LAG3, an antibody that inhibits TIGIT, a checkpoint target blocking antibody, a co-stimulatory antibody, or a CAR-T therapeutic cell.

15. The PD-1 inhibitors or PD-L1 inhibitors include nivolumab, CT-011, AMP-224, pembrolizumab, pidilyzumab, MK-3475, BMS936559, MEDI4736, MSB001071 8C, MPD L-3280A, SHR-1210, IBI308, BGB-A317, JS001, GLS-010, GB226 geptanolimab, HLX10, AK103, AK104, AK105, AK112, SSI-361, JY034, KN035, SHR1316, TQB2450, KL-A167, CS1001, STI-A1014, JS003, AK106, HLX-09, mPD-1 antibodies, The checkpoint target blocking antibodies include IMP321, MGA271; The combination drug according to claim 14, wherein the costimulatory antibody comprises an anti-4-1BB antibody, an anti-OX40 antibody, an anti-GITR antibody, an anti-CD27 antibody, and an anti-CD40 antibody.

16. 14. The combination drug of claim 13, wherein the chemotherapy drug is a toxic drug, an alkylating drug, an antimetabolite, an antibiotic, a hormonal therapy drug, a natural product anticancer drug, a topoisomerase inhibitor, an immunological drug, a platinum complex drug, a kinase inhibitor, an antiproliferative drug, an antibody, an interferon, or a drug that modulates the androgen signaling pathway.

17. The toxic drugs include, but are not limited to, gemcitabine, paclitaxel, and docetaxel; The kinase inhibitors include, but are not limited to, MEK kinase inhibitors, cMet inhibitors, VEGFR2 inhibitors, and EGFR inhibitors; The combination drug according to claim 16, wherein the drug regulating the androgen signaling pathway includes, but is not limited to, an androgen synthesis inhibitor, a CYP17A inhibitor, an androgen receptor inhibitor, a BET inhibitor, a BRD4 inhibitor, a RORγ inhibitor, a CBP / P300 inhibitor, a BMX inhibitor, and a PARP inhibitor, and preferably, the androgen receptor inhibitor includes, but is not limited to, enzalutamide, apalutamide, bicalutamide, abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ-63576, TAS-3681, HC-1119, proxialutamide, and SHR3680.

18. Use of the combination drug according to any one of claims 12 to 17 in the preparation of a drug for treating cancer.

19. the cancer is a solid tumor; The solid tumors include mesothelioma, pancreatic cancer, soft tissue tumors, metastatic tumors, non-solid tumors, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal cancer, genitourinary cancer, prostate cancer, ovarian cancer, the gastrointestinal cancer including colon cancer, the genitourinary cancer including renal, urothelial or testicular cancer, the ovarian cancer including advanced ovarian cancer; The mesothelioma includes neurofibroma, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma, neuroma, adenoid cystic carcinoma, ependymoma, ependymal tumor, malignant pleural tumor, malignant pleural mesothelioma, triplomas, negative breast cancer, non-hematological malignancies, melanoma, colorectal cancer, leukemia, adenocarcinoma, solid tumors; 19. The use of claim 18, wherein the melanoma includes locally advanced melanoma, locally mutated N-Ras-driven melanoma, metastatic malignant cutaneous melanoma, the colorectal cancer includes metastatic colorectal cancer, the leukemia includes acute myeloid leukemia, the adenocarcinoma includes adenocarcinoma, and the solid tumors include locally advanced solid tumors, metastatic solid tumors, and hepatocellular carcinoma.

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